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Transcriptional regulation and the role of diverse coactivators in animal cells

Transcriptional regulation and the role of diverse coactivators in animal cells

Transcriptional regulation and the role of diverse coactivators in animal

FEBS 29150 FEBS Letters 579 (2005) 909–915 Minireview Transcriptional regulation and the role of diverse coactivators in animal cells Robert G. Roeder Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA Received 6 December 2004; revised 7 December 2004; accepted 7 December 2004 Abstract Transcriptional regulation in eukaryotes involves structurally and functionally distinct nuclear RNA polymerases, corresponding general initiation factors, gene-specific (DNAbinding) regulatory factors, and a variety of coregulatory factors that act either through chromatin modifications (e.g. histone acetyltransferases and methyltransferases) or more directly (e.g. Mediator) to facilitate formation and function of the preinitiation complex. Biochemical studies with purified factors and DNA versus recombinant chromatin templates have provided insights into the nature and mechanism of action of these factors, including pathways for their sequential function in chromatin remodeling and preinitiation complex formation/function (transcription) steps and a possible role in facilitating the transition between these steps. Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Keywords: Transcriptional activators; Coactivators; RNA polymerase II; Mediator; Histone acetyltransferases; Histone methyltransferases 1. Introduction and historical perspective Eukaryotic genomes are complex (up to 25 000 genetic loci in human) and organized within compact nucleoprotein (chromatin) structures. The mechanisms by which individual genes are activated are of intense interest and physiological importance, and studies over the past 35 years have revealed several levels of control [1]. First, eukaryotes contain three functionally distinct classes of nuclear RNA polymerases [2] that selectively transcribe large ribosomal RNA genes (RNA polymerase I), proteincoding and some small structural RNA genes (RNA polymerase II) and tRNA, 5S RNA and other small structural RNA genes (RNA polymerase III) [3,4]. These specificities are reflected in the structurally distinct subunit compositions of the three RNA polymerases [5], which contain both common subunits and unique subunits related to those of the bacterial RNA polymerase [6], and allow for independent global regulation of the major classes of RNA. Second, eukaryotic cells contain RNA polymerase-specific general initiation factors that, despite the structural complexity E-mail address: roeder@rockefeller.edu (R.G. Roeder). Available online 15 December 2004 Edited by Gunnar von Heijne and Anders Liljas of the enzymes (14, 12 and 17 subunits in RNA polymerases I, II and III, respectively), are necessary for accurate transcription initiation on corresponding core promoter elements by purified RNA polymerases [7–11]. These factors are now known to include TFIIIC and TFIIIB for RNA polymerase III [reviewed in 12]; TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH for RNA polymerase II [reviewed in 13]; and several factors for RNA polymerase I [reviewed in 14]. Following identification of core promoter recognition factors (TFIIIC for class III and TFIID for class II promoters), mechanistic studies revealed pathways for the ordered assembly of initiation factors and RNA polymerases into corresponding preinitiation complexes (PICs) [15–18] (Figs. 1, left, and 2, right). The structural complexity of the basic preinitiation complexes ( 25 and 44 polypeptides, respectively, for RNA polymerases III and II) is remarkable; and a variety of biochemical and genetic analyses have provided much detail regarding the structure and function of the individual polypeptides during PIC formation and during subsequent transcription initiation and post-initiation events [12–14]. In the case of RNA polymerase II, additional insights into PIC formation and RNA polymerase function have been provided by structural studies of TBP- TATA and higher order complexes [reviewed in 19] and of RNA polymerase II itself [6,20]. Given that RNA polymerases and general initiation factors are the ultimate targets of regulatory factors, these complex assembly pathways offer many points for regulatory interactions. In this regard, it is important to note that while purified RNA polymerases and corresponding general initiation factors (comprising the basal transcription machinery) have an intrinsic ability to accurately transcribe DNA templates through core promoter elements, thus allowing the fundamental transcription mechanisms to be elucidated, these activities are generally suppressed in the cell by the packaging of DNA within chromatin and by negative cofactors that directly interfere with the function of the basal transcription factors (Fig. 3). As discussed below, this imposes requirements for transcriptional activators and corresponding cofactors that act in a gene-specific manner both to reverse the repression (antirepression) and to effect a net activation above the intrinsic activity of the basal transcription machinery (Fig. 3). Third, eukaryotes contain diverse sequence-specific DNA binding transcriptional regulatory factors that facilitate RNA polymerase function on corresponding target genes. The 5S gene-specific TFIIIA was the first of these to be identified as such, purified and cloned [21,22], and also represents the prototype zinc finger protein [23]. [Zinc finger proteins are the 0014-5793/$30.00 Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2004.12.007

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